The major causes of physical disability (arthritis, osteoporosis, stroke, lupus, inflammatory bowel disease, asthma, allergy), mental deterioration (Alzheimer's disease, Vascular dementia, depression, Parkinson's disease), and death (cardiovascular disease, diabetes, cancer), all are initiated and propagated by systemic inflammation (Brod 2000; Thomas 2003). Under normal conditions inflammation is a response to injury and has a major role in immune function and tissue repair. A dysregulation of the inflammatory mechanism may occur with aging or infection, and the influence of environmental and genetic factors. Mediators of inflammation such as C-reactive protein, cytokines, adhesion molecules, and metaloptoteinases may also contribute to the development and progression of inflammatory processes. Thus reduction of levels of inflammatory markers may indicate amelioration of the inflammatory process and reduced risk for inflammatory diseases. A number of antiinflammatory drugs are currently used and new agents are being developed for the prevention and treatment of inflammatory disorders. Antiinflammatory agents are the most widely used class of medications world-wide. The major drugs with antiinflammatory action are nonsteroidal antiinflammatory drugs (NSAIDS), steroids, acetaminophen (COX-3 inhibitors), 5-lipoxygenase inhibitors, leukotriene receptor antagonists, leukotriene A4 hydrolase inhibitors, angiotensin converting enzyme antagonists, beta blockers, antihistaminics, histamine 2 receptor antagonists, phosphodiesterase-4 antagonists, cytokine antagonists, CD44 antagonists, antineoplastic agents, 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins), estrogens, androgens, antiplatelet agents, antidepressants, Helicobacter pylori inhibitors , proton pump inhibitors, thiazolidinediones, dual-action compounds, combinations of these drugs with other agents, derivatives and metabolites of synthetic and natural antiinflammatory agents.
Nonsteroidal Antiinflammatory Drugs (NSAIDS)
NSAIDS are a group of drugs that, despite significant differences in their chemical structure and pharmacological profile, share common activities such as antiinflammatory, analgesic, antipyretic and antiplatelet actions. The NSAIDS are the most widely consumed drugs worldwide, with an estimated 50-60 million individuals in the United States alone using them on a regular basis. Novel actions of aspirin and other NSAIDS are increasing the number of individuals using these compounds. NSAIDS are increasingly being used for the prevention and/or treatment of arthritis, inflammation, gout, pain, fever, and cardiovascular disease, complications of diabetes, stroke, cancer, Alzheimer's disease and dementia (Patrono, 2001; Gupta 2001, In'T Veld, 2001). An aspirin resistance syndrome has been described in some patients taking aspirin (Hankey, 2004). NSAIDS also provide protection against degenerative diseases by reducing the production, aggregation and deposition of amyloidogenic proteins like amyloid-beta, and amylin (Thomas, 2001, 2003)
Even though NSAIDS have several biological actions, their major beneficial effects are considered to be mediated through the inhibition of the enzyme cyclooxygenase (COX) responsible for conversion of arachidonic acid to prostaglandins. Cyclooxygenase exists in two unique isoforms encoded by separate genes and exhibits distinct patterns of tissue-specific expression. COX-1 is primarily expressed constitutively and functions as a physiologic “housekeeping enzyme” in most tissues including gastric mucosa, the kidneys and platelets. COX-2 expression, especially in macrophages and synovial cells is induced by inflammatory stimulus (Emery, 2001). Commonly used NSAIDS inhibit both COX-1 and COX-2 enzymes to varying degrees. But recent evidence indicates that COX 2 is also constitutively expressed in many tissues (Hennan et al., 2000) and the inhibition of COX-2 may induce endothelial dysfunction. The therapeutic benefits of conventional NSAIDS are believed to be derived from the inhibition of COX-2, while the adverse effects, particularly gastrointestinal toxicity, occur as a result of their effects on COX-1. This has led to the development of a new class of compounds, which selectively inhibits COX-2 only and may have a reduced level of gastrointestinal side effects compared to conventional NSAIDS.
NSAID Toxicity
Despite impressive therapeutic benefits, NSAID use places individuals at a risk for several serious complications such as gastrointestinal (GI) toxicity, renal damage and platelet dysfunction (Fennerty, 2001; Gramlich, 2001; Rocha et al, 2001). The major complication is gastrointestinal toxicity, which has a wide array of clinical manifestations ranging from dyspeptic symptoms to life-threatening intestinal bleeding or perforation of gastro duodenal mucosa and gastric outlet obstruction (Wolfe et al; 1999). The gastrointestinal toxicity is evident even at low doses of aspirin used for prevention of myocardial infarction. In fact NSAID toxicity is considered to be the number one cause of drug-induced complications. NSAID-related ulcer complications lead to up to 400,000 hospitalizations and 16,500 deaths yearly in the United States. Concomitant administration of other NSAIDS along with aspirin also reduces the anti-platelet and cardiovascular benefits of aspirin by interfering with cyclooxygenase inhibition (Catella-Lawson, 2001).
The toxic effects of NSAIDS may be mediated by reduced gastric mucosal blood flow, neutrophil adhesion, free radical generation, and reduced mucous secretion as shown below.

NSAID-induced gastropathy involves topical irritant effects on the epithelium as well as the deleterious effects of inhibition of prostaglandin synthesis. Loss of prostaglandin-mediated protection makes the gastric mucosa susceptible to damage induced by acid or other irritants. The effects of NSAID on gastric microcirculation is considered to be the most important factor leading to mucosal injury (Wallace 2003). NSAIDS reduce gastric mucosal blood flow through endothelial damage, neutrophil adhesion, liberation of oxygen radicals and capillary obstruction.
Deprenyl and related compounds have the ability to prevent NSAID-induced gastric damage through enhancing blood flow, prevention of neutrophil adhesion, reducing free radical toxicity, endothelial protection, stimulation of antioxidant enzymes, and antiinflammatory actions.
Several strategies have been employed to reduce the gastrointestinal toxicity caused by NSAIDS (Lanas, 2001). These include enteric coating to prevent absorption in the stomach, parental administration, use of pro-drugs that require hepatic metabolism to produce cyclooxygenase inhibition, co administration of gastro protective agents (proton pump inhibitors, histamine-2 receptor antagonists, prostaglandins), COX-2 specific drugs, and nitric oxide releasing NSAIDS (Wallace, 1999; 2003; Yeomans, 2001). All of these methods have significant limitations and have not significantly reduced the incidence or complications of NSAID toxicity. For example COX-2 inhibitors are not devoid of GI toxicity, may cause hypertension and edema, and do not inhibit platelet thromboxane production. In addition COX-2 derived prostacyclin has important cardioprotective effects and inhibition of this activity may increase the risk of acute vascular events in patients receiving these drugs (Hennan 2000, Mukherjee 2001). The nitric oxide releasing NSAIDS produce only local effects. The nitric oxide is released locally in the stomach and has short half-life of less than 30 seconds. Therefore it will not provide long periods of protection and also will not prevent the toxic effect of NSAIDS of other targets such as the kidney. Thus there is an urgent need to develop new methods to prevent, reduce or reverse NSAID toxicity.
COX-3 Inhibitors
The COX-3 inhibitor acetaminophen (Tylenol) is widely used analgesic and antipyretic drug. At high doses acetaminophen is toxic to liver, kidney, and other tissues. Acetaminophen may cause cell damage by stimulating apoptosis through mitochondrial damage, and generation of toxic oxygen radicals and peroxynitrite (James 2003; Boulares 2002).SteroidsGlucocorticoids are agents used in a number of disorders like asthma, rheumatoid arthritis and psoriasis. This group includes short-acting agents (cortisone, hydrocortisone), intermediate-acting agents (prednisone, methylprednisone, triamcinolone), and long-acting agents (dexamethasone, betamethasone). Glucocorticoid use is associated with complications such as weight gain, hypertension, Cushingoid facies, diabetes mellitus, osteoporosis, myopathy, increased intraocular pressure, ischemic bone necrosis, infection, hypercholestolemia. exacerbation of peptic ulcer, gastritis and esophagitis.Lipoxygenase InhibitorsThe metabolism of arachidonic acid by lipoxygenase pathway generates leukotrienes. Leukotrienes generated by 5-lipoxygenase activity are proinflammatory. They increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes to the inflammatory site (Lotzer 2003). 5-lipoxygenase inhibitors (eg. Licofelone) are being tested as antiinflammatory agents. These compounds have toxic effects on a number of tissues.Leukotriene ModifiersLeukotrienes formed by the 5-lipoxygenase pathway have a major role in altering the biology of airway wall in asthma. Leukotriene modifiers including leukotriene receptor antagonists, and leukotriene A4 hydrolase inhibitors, are currently used in the treatment of asthma. Examples of leukotriene receptor antagonists are montelukast, pranlukast, and zafirlukast. These drugs inhibit smooth-muscle constriction, eosinophil migration, and edema in airway.AntihistaminesAllergic rhinitis is an inflammatory condition of the nose characterized by sneezing, rhinorrhea, and obstruction of nasal passages. Antihistamines like chlorpheniramine, astemizole, and loratidine are used to treat allergic rhnitis.Phosphodiesterase InhibitorsType 4 phosphodiesterases (PDE4) belong to a superfamily of at least 11 isoenzymes catalyzing the hydrolysis of second messengers cyclic AMP and/or cyclic GMP. PDE4 regulates the intracellular levels of cyclic AMP and are the major PDE expressed in inflammatory cells (Jacob 2002, Zhu 2001). The vide range of inflammatory mechanisms regulated by PDE4 makes this enzyme an attractive target for antiinflammatory drugs. PDE4 inhibitors have been shown to be effective in the treatment of chronic inflammatory diseases like asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, cancer, hepatitis, autoimmune disease, brain inflammation, and endogenous depression.PDE4 inhibitors have behavioral and other side effects like nausea and emesis.StatinsStatins (HMG-CoA reductase inhibitors) are widely used to lower lipid levels and accord protection against cardiovascular disease. Recent evidence indicates that some of the benefits of statins are due to non-lipid mechanisms. A major component of the pleiotropic effects of statins is considered to be due to their antiinflammatory action (Werner 2002). Most of the currently available statins have the potential to cause complications (Muscari 2002). The complications include altered liver function, skeletal muscle and peripheral nerve changes, flu-like symptoms, weakness, aching muscles and joints. The major side effect is myopathy, rhabdomyolysis and ensuing acute renal insufficiency.EstrogensPostmenopausal women have a higher incidence of inflammatory disorders including cardiovascular disease, arthritis, and Alzheimer's disease, possibly due to estrogen deficiency. A number of reports have indicated that the beneficial effects of estrogen may be partly due to antiintlammatory activity (Thomas, 2003).But estrogen use is associated with a number of side effects. The adverse events include elevation of CRP level, increased cardiovascular events, stroke, thromboembolism, cancer, and dementia (Writing group for WHI, 2002).ThiazolidinedionesThiazolinediones like rosiglitazone and pioglitazone are used in the treatment of diabetes. The action of these drugs is partially mediated by their antiinflammatory action as they reduce the levels of several markers of inflammation including CRP.Combination DrugsSeveral dual acting and combination antiinflammatory drugs are currently in use, These include combinations of NSAIDS or other antiinflammatory agents with other drugs. Examples of such combination drugs include Aggrenox (aspirin+dipyridamole), Darvon (aspirin+propoxyphene+caffeine), Excedrin (aspirin+actaminphen+caffeine), Percodan (aspirin+oxycodone), Soma (aspirin+carisprodol), Synalogos (aspirin+dihydrocodeine+caffeine), Butabital (aspirin+caffeine+codeine), Norgesic (orphenadrine+caffeine), (see Physicians Desk Reference 2003, page 103 for complete list); aspirin+statins, aspirin+antioxidants, aspirin+vitamins, aspirin+steroid hormones, NSAID+5-lipoxygenase inhibitors, or NSAID+phosphodiesterase-4 inhibitors.
This invention relates to methods and compositions to ameliorate antiinflammatory drug toxicity by using inhibitors of monoamine oxidase (MAO) enzymes. Monoamine oxidases catalyze the deamination of monoamines. MAO exists in two different forms, MAO-A and MAO-B, encoded by two distinct gene loci, with different patterns of tissue distribution (Knoll et al; 1972, Shih 1991). MAO-A preferentially deaminates serotonin and is more sensitive to inhibition by clorgyline, whereas MAO-B preferentially deaminates β-phenylethylamine and is inhibited by drugs such as 1-deprenyl. The MAO-B inhibitor 1-deprenyl is effective in the treatment of Parkinson's disease, Alzheimer's disease and depression, and has been found to extend the life span (Knoll 1989, Birkmayer 1985).
It is now evident that the therapeutic efficacy of 1-deprenyl may involve cytoprotective actions other than the inhibition of MAO-B. These include a variety of biological actions such as neuroprotection, endothelial protection, anti-inflammatory activity, antioxidant action, free radical scavenging, antiapoptotic action, up-regulation of growth factors like NGF, BDNF, and GDNF (Mizuta 2000), reduction of hypoxia, reduction of oxidative stress, antagonism of cytotoxic actions of toxic agents such as amyloid-β peptide, inhibition of tumor growth, vasodilation, increased blood flow, inhibition cytochrome P450 enzymes (Dycek 2000) enhanced expression of antioxidant enzymes (Thomas 2000, Carillo 2000, Surronen 2000, Thyagarajan 2000) and stimulation of constitutive nitric oxide synthase enzymes resulting in the enhanced production of nitric oxide (Thomas 1998). A combination of these actions contributes to the ability of MAO inhibitors to ameliorate the toxic effects of NSAIDS and provide tissue protection (Galvin, 1986).